Investigating developmental therapeutics for children with solid malignancies and CNS tumors
Anticancer drugs offer therapeutic benefits in children with solid malignancies and central nervous system (CNS) tumors. Yet, how these drugs act once they enter a child’s body is not well understood. If we can enhance our understanding of drug activity in the body, we can help guide more effective treatments for children. Our work measures the CNS penetration of anticancer drugs and their subsequent activity. To achieve this, we use models that simulate drug regimens (e.g., dosage and schedule) and response. Our goal is to identify anticancer regimens for drugs that are safe and effective in the treatment of solid malignancies and CNS tumors in children.
Our research efforts focus on developmental therapeutics for children with solid malignancies and CNS tumors. Our lab uses subgroup-specific models of pediatric CNS tumors, cerebral microdialysis, and pharmacokinetic modeling and simulation to assess the penetration of drugs used to treat pediatric CNS tumors. Since little is known about the disposition of anticancer agents in children, we apply pharmacologic approaches in clinical trials to understand the variability of drug disposition. These results integrate into dosing regimens that account for interpatient variability, help achieve desired pharmacologic goals, and enable a more uniform systemic exposure to anticancer drugs across all pediatric age groups.
A key area of focus in our laboratory is understanding how drugs penetrate the brain. Through collaborative efforts with other laboratories in the Department of Developmental Neurobiology and the Department of Tumor Cell Biology, we use microdialysis to study the cerebral pharmacokinetics of drugs in experimental models. Microdialysis allows us to sample tumor extracellular fluids as well as plasma in experimental models, which enables us to measure the unbound drug concentration using binding studies and mass spectrometry. The ability to measure the active (unbound) drug concentration, which is the amount of drug not bound to a protein, allows us to capture a more accurate picture of the drug’s effect on a target receptor. Through this accurate measurement of unbound drug concentration in cerebral fluids, we can discern the unbound drug coefficient, which provides a good idea of the quantity of drug penetration into the brain. We share this information with preclinical investigators to help determine whether a particular drug is a good candidate for pre-efficacy studies. As our approach studies a variety of tumor types in the forebrain and ventricle, our work leads to pharmacokinetic information that helps shape potential pharmacologic therapies for multiple disease types.
Drug optimization in pediatric brain tumor treatment
A vital and rewarding component of our laboratory is our translational work. What we learn in the lab, we share with clinicians to improve therapies for childhood cancer patients. To achieve this translational approach, we conduct studies to optimize the use of drugs in the treatment of children with brain tumors. Our laboratory spends a considerable amount of time developing clinical protocols and conducting clinical pharmacokinetic analyses in collaboration with clinicians and pharmacologists.
In our research with the anticancer chemotherapy drug, gemcitabine, our goal is to create a semi-physiological pharmacokinetic model to deepen our understanding of the disposition of the drug in children with brain tumors. On the preclinical side, we examine different dosages of gemcitabine in a preclinical model to measure the drug and its metabolite, difluorodeoxyuridine (dFdU), within the normal brain, brain tumor, and plasma. We additionally measure the metabolized component gemcitabine triphosphate in the brain and peripheral blood mononuclear cells (PBMC). Moreover, we conduct studies of the pharmacodynamic effects of gemcitabine triphosphate-induced DNA damage and apoptosis. In a stepwise approach, these murine gemcitabine pharmacokinetic and pharmacodynamic data are integrated into a semi-mechanistic pharmacokinetic model.
We currently have three ongoing clinical trials in children with brain tumors who are receiving gemcitabine. We are conducting plasma pharmacokinetic studies as well as measuring gemcitabine triphosphate in PBMCs. As we have done in the murine model, we plan to integrate the gemcitabine pharmacokinetic data into a semi-mechanistic pharmacokinetic model, and then will link the two models into a translational model. This translational model will allow us to estimate the most effective gemcitabine dosage for treatment of children with brain tumors.
In our lab, translational research is a foundation of our work, and the mission of St. Jude drives our team of researchers to contribute to the unified goal of curing children with cancer.